Friday, November 30, 2012

How will taking Doxycycline affect your height?

There's a lot of contradictory information on doxycycline.  But, it's clear that doxycycline has an effect on chondrocyte hypertrophy with a definite effect on MMP13 and a possible effect on Col10.  A reduction of MMP13 in the growth plates has been linked to one form of dwarfism.  MMP13 is likely biphasic where there's an optimal quantity for growth.  Doxycycline is a commonly prescribed acne medication.  It's clear that doxycycline will affect your height growth but it's not clear how.

Effects of Doxycycline on Mesenchymal Stem Cell Chondrogenesis and Cartilage Repair.

"Ninety hMSC pellets were cultured in chondrogenic media with either 0-, 1- or 2-μg/mL doxycycline. Osteochondral defects (OCD) were created in the trochlear grooves of 24-Sprague-Dawley rats treated with/without oral doxycycline. Rats were sacrificed at 12-weeks.
hMSC pellets with 1-μg/mL=and 2-μg/mL doxycycline had larger areas than pellets without doxycycline. hMSC pellets with 2-μg/mL doxycycline showed reduced mmp-13 mRNA and protein at 21-days. Proteoglycan, DNA contents, and mRNA expressions of chondrogenic genes were similar. For the in vivo study, while the histological scores were similar between the two groups, the gross scores of the OCD repair tissues in doxycycline-treated rats were higher at 12-weeks, reflective of improved repair quality. The doxycycline-treated repairs also showed lower MMP-13 protein.
Doxycycline improves hMSC chondrogenesis and decreases MMP-13{MMP-13 may have beneficial effects on endochondral ossification however} in pellet cultures and within rat OCDs. Doxycycline exerted no negative effect on multiple measures of chondrogenesis and cartilage repair."

"Microfracture (bone marrow stimulation) is commonly used to treat focal cartilage injuries. This technique involves the recruitment of bone marrow derived mesenchymal stem cells (MSCs) to the defect area to participate in cartilage repair. However, the resulting repair does not restore hyaline articular cartilage, but instead results in formation of a mechanically inferior fibrocartilaginous scar tissue"<-Maybe this is why people didn't get taller with microfracture theory?  If microfracture within bones results in the same fibrocartilaginous scar tissue.

"Oral administration of doxycycline has been postulated to have beneficial effects on articular cartilage by inhibiting MMP, specifically MMP-1, -3 (stromelysin), and -13"

"[Comparisons of} joint space narrowing in mildly arthritic knees, [revealed] the doxycycline treatment group had a decreased rate of narrowing by 40% at 16-19 months and 33% at 30-months as compared to placebo"<-This would be a significant reduction in height loss in the mature individuals.

Doxycycline only affected MMP-13 and not Sox9, Aggrecan, Col2a1, Col10a1, and TGFBRII.  Doxycycline had a greater effect on MMP-13 after 21 days in chondrocyte culture at 2 micrograms per millilieter.

"the pellet areas in the 2-μg/mL doxycycline group were larger than those in no doxycycline treatment group."  Since doxycycline does not reduce Col10 levels it's possible that Doxycycline could inhibit MMP-13 without affecting chondrocyte hypertrophy thus having a purely beneficial effect on height.

Influence of doxycycline on the epiphyseal plate cartilage of the rats in experimental osteoarthrosis, induced by iodoacetate.

"In 36 Wistar rats with the iodoacetate-induced experimental osteoarthrosis (OA), effects of doxycycline, given orally, were determined on histochemical reactions of glycosaminoglycans (GAG) in the epiphyseal plate cartilage. The epiphyseal plate of rats with OA was reduced in height (especially the proliferative zone), cell columns were disorganized, many chondrocytes were irregular and polygonal, their nuclei were pycnotic, the intensity of GAG staining was irregular and predominantly reduced, which can be interpreted as signs of degeneration. A concomitant administration of doxycycline in the second group of rats prevented, to some extent, the negative effects of iodoacetate on chondrocytes and led to a more pronounced intensity of GAG reactions in the matrix of the epiphyseal plate."

"in some rats, treated with doxycycline, we observed signs of focal chondrocyte proliferation and of matrix GAG production"

Regulation of cartilage collagenase by doxycycline.

"Chondrocytes were isolated from human OA cartilage and treated with doxycycline. 
We observed significant inhibition of matrix metalloproteinases (MMP-1) and MMP-13 mRNA and protein production by chondrocytes, isolated from OA cartilage, after treatment with doxycycline. The decrease in collagenase protein level paralleled a decrease in mRNA for these enzymes, suggesting a transcriptional/posttranscriptional level of control. In addition, treatment with 10 microg/ml doxycycline resulted in 2.2-fold upregulation of transforming growth factor (TGF-beta3) and a significant decrease of interleukin 1alpha (IL-1alpha), IL-1beta, and IL-6 mRNA. Upregulation of TGF-beta RI and TGF-beta RII was also detected. These cytokines are known to affect collagenase expression and could contribute to inhibition of MMP-1 and MMP-13 production by OA chondrocytes. A decrease in IL-1alpha, IL-1beta, and IL-6 would reduce stimulation of MMP production, while an increase in TGF-B3 would lead to downregulation of local proinflammatory cytokine production as well as of the collagenases themselves.
Our findings show that a decrease in MMP-1 and MMP-13 collagenase production by articular chondrocytes in response to treatment with doxycycline can be explained by a regulatory effect of doxycycline on the production of cytokine and cytokine receptors."

Couldn't get full text.

"To investigate the ability of doxycycline, transforming growth factor beta1 (TGFbeta1), and phorbol myristate acetate (PMA) to modulate collagenase synthesis in osteoarthritic (OA) chondrocytes.
Levels of fibroblast collagenase (matrix metalloproteinase 1 [MMP-1]), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13) proteins and messenger RNA (mRNA) were measured in chondrocytes isolated from involved and uninvolved areas of OA cartilage and from normal human chondrocytes, after treatment with doxycycline, TGFbeta1, and PMA.
Chondrocytes isolated from cartilage immediately adjacent to the OA lesion had, on average, 1.8-3.9-fold higher basal levels of MMP mRNA. These cells down-regulated collagenase proteins and mRNA upon incubation with TGFbeta1. In contrast, chondrocytes from areas located more distant from the macroscopic lesion increased MMP-13 mRNA, while MMP-1 and MMP-8 decreased after stimulation with TGFbeta1. Discoordinate regulation was observed after stimulation with PMA, with an increase in MMP-1 and MMP-8 but a decrease in MMP-13. Incubation of OA chondrocytes with doxycycline (1-10 microg/ml), at pharmacologically achievable levels, decreased levels of mRNA of all 3 collagenases, but not G3PDH. In addition, doxycycline inhibited the increase in mRNA for these enzymes in normal chondrocytes stimulated with tumor necrosis factor alpha.
Regulation of MMP-1, MMP-8, and MMP-13 in OA chondrocytes, although mediated by differing pathways, can be decreased by treatment with doxycycline at low concentrations."

"Chondrocytes from normal-appearing cartilage stimulated with TGFb1 showed enhanced synthesis of MMP-13."<-this shows the possible important of MMP-13 to normal processes.

Doxycycline inhibits collagen synthesis by differentiated articular chondrocytes.

"Doxycycline (DOX) profoundly inhibited collagen synthesis by differentiated articular chondrocytes. At 25 microM, the rate of collagen synthesis was suppressed by more than 50% without affecting cell proliferation and general protein synthesis. Steady-state mRNA levels of type II collagen were also reduced, indicating that DOX may have an effect at the transcriptional level of type II collagen. The IC50 value of DOX to downregulate collagen synthesis (17 microM) is close to DOX levels attained in vivo (< 10 microM), and it is more than ten-fold lower than the IC50 values to inhibit the activity of most matrix metalloproteinases (MMPs). As such, these findings support the hypothesis that the reduced severity of OA observed in the dog anterior cruciate ligament model resulting from prophylactic treatment with DOX may involve mechanisms other than MMP inhibition alone. Our findings suggest that prevention of changes in the chondrocyte phenotype may be involved in the beneficial effect of doxycycline in experimental osteoarthritis, for differentiated chondrocytes in early stages of osteoarthritis exhibit elevated collagen synthesis."

"Increased synthesis of type II collagen is a characteristic of early stages of OA"

Doxyclycline inhibits collagen synthesis by bovine chondrocytes cultured in alginate.

"doxycycline exhibits a profound inhibition of collagen synthesis by bovine articular chondrocytes cultured in alginate. At 25 microM doxycycline, collagen synthesis was decreased by 50%; no effect on cell proliferation or general protein synthesis was observed. Messenger RNA levels of type II collagen were also reduced, indicating an effect of doxycycline at the transcriptional level. The concentration of doxycycline needed to downregulate collagen synthesis was > 10-fold lower than that needed to inhibit most of the MMPs. In asmuch as differentiated chondrocytes in the early stages of osteoarthritis exhibit increased collagen synthesis, the beneficial effect of doxycycline in vivo may involve prevention of changes in chondrocyte phenotype."

Doxycycline disrupts chondrocyte differentiation and inhibits cartilage matrix degradation.

"The effects of doxycycline were tested in an in vitro system in which the cartilages of embryonic avian tibias are completely degraded.
Tibias were cultured with 5, 20, or 40 microgram/ml doxycycline. Control tibias were cultured without doxycycline. Conditioned media and tissue sections were examined for enzyme activity and matrix loss.
Cartilages were not resorbed in the presence of doxycycline, whereas control cartilages were completely degraded. Collagen degradation was reduced in association with treatment with doxycycline at all doses studied. Higher concentrations of doxycycline reduced collagenase and gelatinase activity and prevented proteoglycan loss, cell death, and deposition of type X collagen in the cartilage matrix; in addition, treatment with doxycycline at higher concentrations caused increases in the length of the hypertrophic region.
The effects of doxycycline extend beyond inhibition of the proteolytic enzymes by stimulating cartilage growth and disrupting the terminal differentiation of chondrocytes."

"in the tibias cultured with 40pg/ml doxycycline, not all of the chondrocytes had undergone hypertrophy. At the proximal ends of the cartilages, there remained a population of small, flattened cells that had not become hypertrophic"

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